PHA/NHLBI K08/K23 Award Winner 2012

Oracle Corporation Community Grant

Vinicio A. de Jesus Perez, MD

Division of Pulmonary and Critical Care MedicineDepartment of MedicineStanford University Medical Center"The role of the Wnt/planar cell polarity pathway in pulmonary angiogenesis"NHLBI Mentored Clinical Scientist Development Award (K08)Term: July 1, 2012 – June 30, 2017

Summary of Research Project:

The role of the Wnt/planar cell polarity pathway in pulmonary angiogenesis

In 2012, Dr. de Jesus Perez was awarded an NIH K08 award to investigate a novel mechanism relevant to the regeneration of pulmonary vessels following injury. This is relevant to idiopathic pulmonary arterial hypertension (IPAH) as progressive narrowing and loss of small distal pulmonary arteries is a key pathological finding in all patients who are afflicted with this devastating disease.

Recent studies by our group and others have shown that mutations in the bone morphogenetic protein receptor (BMPR) II could contribute to vessel loss by reducing pulmonary artery endothelial cell (PAEC) survival and proliferation in response to injury but the mechanisms by which BMPRII can regulate these angiogenic responses have not been well characterized. In addition to PAECs, pericyte recruitment is critical for stabilization of newly formed vessels but their contribution to the pathogenesis of IPAH has not been well established. We have recently shown that BMP signaling promotes pulmonary angiogenesis by recruitment of two Wnt signaling pathways in PAECs: the “canonical” Wnt/β-catenin (βC) and the “non-canonical” Wnt/planar cell polarity (PCP) pathways.

Based on our preliminary studies and our review of the literature, we propose that activation of the Wnt/PCP pathway is required for pulmonary angiogenesis by 1) inducing PAEC to organize into properly aligned vascular tubes and 2) by promoting pericyte recruitment to vascular tubes to form functional blood vessels. In a series of experiments using PAECs and pericytes obtained from the lungs of healthy donors and IPAH patients, we will demonstrate that Wnt/PCP signaling is required to direct PAEC (Aim 1) and pericyte (Aim 2) behavior during angiogenesis and that loss of activity correlates with reduced pulmonary angiogenesis. Furthermore, we will complement these cell studies with work on two animal models of dysfunctional Wnt/PCP signaling that will help provide insight into the biological relevance of this pathway to compensatory angiogenesis following pneumonectomy (Aim 3).

Future studies will center on how mutations that reduce Wnt/PCP signaling can genetically interact with BMPRII mutations to promote development of IPAH and how therapeutic interventions aimed at normalizing Wnt/PCP pathway activity in PAEC and pericytes could help prevent progression and improve survival in IPAH patients by restoring their ability to regenerate lost vessels.

CURRICULUM VITAE

Name: Vinicio A. de Jesus Perez, MD

Assistant Professor of MedicineDivision of Pulmonary and Critical Care MedicineDepartment of MedicineStanford University School of Medicine300 Pasteur Drive, Grant S140BStanford, CA 94305Email: vdejesus@stanford.edu

Last reviewed: October 2012

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